The present invention is directed to methods and compositions that are effective to enhance transport of biologically active agents, such as organic compounds, polypeptides, oligosaccharides, nucleic acids, and metal ions, across biological membranes.
The plasma membranes of cells present a barrier to passage of many useful therapeutic agents. In general, a drug must be freely soluble in both the aqueous compartments of the body and the lipid layers through which it must pass, in order to enter cells. Highly charged molecules in particular experience difficulty in passing across membranes. Many therapeutic macromolecules such as peptides and oligonucleotides are also particularly intractable to transmembrane transport. Thus, while biotechnology has made available a greater number of potentially valuable therapeutics, bioavailability considerations often hinder their medicinal utility. There is therefore a need for reliable means of transporting drugs, and particularly macromolecules, into cells.
The present invention is based in part on the applicants' discovery that conjugation of certain oligomers or polymers to small molecules or macromolecules is effective to significantly enhance transport of the attached molecule across biological membranes. The transport reagents contain highly basic subunits either interrupted by neutral subunits or having a longer backbone to provide suitable spacing between the basic groups (e.g., guanidino or amidino groups).